ABSTRACT Creatine Safety, Tolerability, and Efficacy in Huntington's Disease: CREST-E This is a competing renewal application to complete the ongoing CREST-E clinical trial, which has advanced to Phase III from NCCAM sponsored preclinical and early phase research. CREST-E is an international, multi-center, randomized, double-blind, placebo-controlled, parallel group study involving 650 subjects with Huntington's disease (HD) to assess the efficacy and long-term safety of creatine monohydrate. A companion application is also submitted by Giovanni Schifitto, MD, from the University of Rochester entitled Creatine Safety and Efficacy in HD: Coordination and Statistical Center encompassing site coordination, data management, drug supply, study monitoring, and biostatistics. HD is a dominantly inherited, fatal, neurodegenerative disorder, which no treatment has been demonstrated to slow. About 30,000 Americans have clinical HD, and an additional 150,000 are genetically at risk of developing it. Neurodegeneration in HD involves impaired energy production and oxidative damage. Creatine restores ATP from ADP and evidence from HD mice and prior human studies suggest that doses of up to 40 grams daily may slow the course of HD. The primary hypothesis of CREST-E is that creatine will slow the progressive functional decline in early HD as measured by the annualized rate of change in the UHDRS Total Functional Capacity scale. Secondary measures include changes in motor and cognitive scores and long- term safety and tolerability. Exploratory measures include additional clinical outcomes; cognitive and quality of life measures; and putative biomarkers of disease activity and progression. The study was designed to assess the potential for creatine to achieve a clinically meaningful 20% slowing or better. About 64% of subjects have been enrolled, significant safety concerns have not emerged, and the study has been modified to incorporate variable periods of participation to insure completion of all clinical activity by January of 2016. This project is consistent with the NCCAM mission of exploring CAM therapies with scientifically rigorous studies. If the study is positive it would be a breakthrough in HD research that would change HD clinical care and would spur research into similar compounds for a host of related neurodegenerative diseases. Additionally, the study will provide critical information on the long- term safety of high dose creatine which is widely used among healthy athletes and patients with a variety of neurodegenerative disorders and other diseases.